Freedom from atrial arrhythmia and other clinical outcomes at 5 years and beyond after catheter ablation of atrial fibrillation: a systematic review and meta-analysis

Abstract Aims Catheter ablation of atrial fibrillation (AF) is now a mainstream procedure although long-term outcomes are uncertain. We performed a systematic review and meta-analysis of procedural outcomes at 5 years and beyond. Methods and results We searched PubMed and Embase and after the screening, identified 73 studies (67 159 patients) reporting freedom from atrial arrhythmia, all-cause death, stroke, and major bleeding at ≥5 years after AF ablation. The pooled mean age was 59.7y, 71.5% male, 62.2% paroxysmal AF, and radiofrequency was used in 78.1% of studies. Pooled incidence of freedom from atrial arrhythmia at 5 years was 50.6% (95%CI 45.5–55.7%) after a single ablation and 69.7% [95%CI (confidence interval) 63.8–75.3%) after multiple procedures. The incidence was higher among patients with paroxysmal compared with non-paroxysmal AF after single (59.7% vs. 33.3%, p = 0.002) and multiple (80.8% vs. 60.6%, p < 0.001) ablations but was comparable between radiofrequency and cryoablation. Pooled incidences of other outcomes were 6.0% (95%CI 3.2–9.7%) for death, 2.4% (95%CI 1.4–3.7%) for stroke, and 1.2% (95%CI 0.8–2.0%) for major bleeding at 5 years. Beyond 5 years, freedom from arrhythmia recurrence remained largely stable (52.3% and 64.7% after single and multiple procedures at 10 years), while the risk of stroke and bleeding increased over time. Conclusion Nearly 70% of patients having multiple ablations remained free from atrial arrhythmia at 5 years, with the incidence slightly decreasing beyond this period. Risk of death, stroke, and major bleeding at 5 years were low but increased over time, emphasizing the importance of long-term thromboembolism prevention and bleeding risk management.


Introduction
Atrial fibrillation ( AF ) is the most common heart rhythm disorder encountered in clinical practice and is known to be associated with an increased risk of death and stroke or transient ischaemic attack ( TIA ) . 1 AF patients are also predisposed to bleeding complications given that many are on oral anticoagulant ( OAC ) for the prevention of thromboembolic events. 2 Among different therapeutic options for AF, catheter ablation is shown to be superior to medications in terms of restoring normal sinus rhythm at 1-2 years post-ablation. 3 -5Given the rapid dissemination of this procedure globally, and that patients undergoing AF ablation are often relatively young ( ≤65 years old ) with a low profile of comorbidities, 6 -8 long-term procedural outcomes are of interest for patients and physicians.However, the risk of atrial arrhythmia recurrence and other outcomes in the years beyond the early period is poorly understood.
Most published studies report freedom from atrial arrhythmia recurrence with a prior systematic review of 6167 patients published in 2013, suggesting the risk of recurrence appear to stabilize at 5 years. 9owever, only a few studies included in this meta-analysis reported outcomes at or beyond this period ( six and four studies were included to estimate the incidence of freedom from atrial arrhythmia recurrence at 5 years after single and multiple procedures, respectively ) . 9iven AF can recur, there is a substantial desire to understand equally important clinical outcomes such as the longitudinal risk of mortality, stroke, and major bleeding in these patients yet these risks were not reported in the prior review. 9Other reviews, on the other hand, did not report the time-specific longitudinal risk of these adverse events, making it challenging to interpret their results. 10 -13Moreover, the past decade has seen much more data on long-term outcomes being published, warranting an updated review of clinical outcomes of AF ablation extending to 5 years and beyond that is not limited to just atrial arrhythmia recurrence.
Accordingly, we performed a systematic review and meta-analysis of outcomes at 5 years or longer after AF ablation.We specifically examined the pooled incidence of freedom from atrial arrhythmia recurrence, all-cause mortality, stroke or TIA, and major bleeding events at 5 or more years after ablation.We also examined potential differences in outcomes among different types of AF, ablation energy used, and study design and quality.

Methods
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis ( PRISMA ) protocol. 14

Sea rc h st rategy
Four reviewers ( LN, WL, MW, and PA ) independently searched PubMed and Embase using identical search strategies ( refer to Supplementary material online Appendix Table S1 for more details ) for all eligible studies published until December 2021.All studies reporting outcomes at least 5 years after AF ablation where the main ablation lesion was pulmonary vein isolation ( PVI ) ( either segmental or circumferential ) were included.After excluding duplicate records, we further excluded: ( i ) publications pertaining to editorial comment, review, research letter, author's reply, survey, opinion, clinical update, and study protocols; ( ii ) abstracts and conference proceedings to ensure reliable data extraction; ( iii ) studies about AF but not PVI ( including ablate and pace strategy, right atrial ablation ) ; ( iv ) studies about ablation of other arrhythmias or targets ( septal ablation ) ; ( v ) studies that did not report outcomes of interest ( cost-effectiveness, quality of life, or procedural complications ) or where data about outcomes at 5 years or more could not be extracted; ( vi ) studies focusing on a specific group of AF patients ( specific age group, patients with certain comorbid conditions such as heart failure, hypertrophic cardiomyopathy, valvular heart disease, common pulmonary trunk, extra-pulmonary vein triggers, congenital heart diseases, or those undergoing repeat ablation only ) , or ( vi ) reported solely on outcomes of surgical AF ablation ( studies comparing outcomes between patients undergoing catheter ablation vs. those undergoing surgical ablation were still included ) .Finally, studies that were not performed on humans, where the full text was not written in English or contained the same population reported in an included study were also excluded.LN reviewed all studies while WL, MW, and PA each reviewed approximately a third of eligible studies ensuring that all eligible studies were independently evaluated by at least two reviewers with differences resolv ed by consensus.

Qua lit y assessment
Study quality was assessed using the tool provided by the National Institute of Health Quality which comprises of 14 questions for cohort and controlled-interventional studies and 9 questions for case-series studies. 15he overall quality was graded as good ( when all answers were 'No' ) , fair ( if there were up to two 'No' answers ) , or poor ( if there were at least three 'No' answers ) .Four reviewers ( LN, WL, MW, and PA ) independently evaluated the quality of individual studies with discrepancies resolved by consensus.

Dat a ext raction a nd ma nipulation
Study data were extracted using a standardised extraction form.LN extracted all studies while WL, MW, and PA each independently extracted approximately a third of eligible studies to ensure that data extraction was performed independently by at least two reviewers with conflicts resolved by consensus.Survival data or incidence of non-fatal outcomes were extracted from the text or from Kaplan-Meier curves using the WebPlotDigitizer application. 16The number of events was estimated from the Kaplan-Meier curve by multiplying the number of enrolled patients with the extracted probability of experiencing the event. 17For studies where median and interquartile range ( IQR ) were reported, the mean and standard deviation ( SD ) were estimated using the methods outlined by Wan et al. 18

Primary endpoints
The primary outcome was freedom from atrial arrhythmia recurrence.The definition of atrial arrhythmia recurrence varied among individual studies although most defined it as the occurrence of atrial tachyarrhythmia ( AF, atrial flutter, or atrial tachycardia ) lasting > 30 seconds as per treatment guidelines. 19When the rate of freedom from atrial arrhythmia recurrence with and without antiarrhythmic drugs was reported separately, only the result with the anti-arrhythmic drugs ( AAD ) was included as most studies reported outcomes with AAD only.Freedom from atrial arrhythmia recurrence was reported separately after the index procedure ( single procedure ) and after the last procedure ( multiple procedures ) .
The secondary outcomes included potential clinical sequelae of AF such as all-cause mortality, stroke or TIA, and major bleeding, with the latter relating to the long-term use of anticoagulation.

St atistic a l a na lysis
We reported results of meta-analysis of continuous variables as the pooled mean and the corresponding 95% CI.Meta-analysis of proportions was performed with Freeman-Tukey double arcsine transformation with results reported as pooled proportion and respec tive 95%CI .A Randomeffects model was purposefully chosen due to the differences among studies in the follow-up schedule and methods to monitor arrhythmia recurrence.The I 2 statistic was used to evaluate the heterogeneity among studies and between-study variance τ 2 was calculated using the restricted maximum likelihood estimator. 20

Risk of bias assessment and subgroup analysis
The risk of publication bias was evaluated through visual examination of funnel plots and Egger's test was used to test for the presence of plot asymmetry. 21Where Egger's test indicated possible funnel plot asymmetry, a leave -one -out analysis was performed to identify the effect of leaving one study out of the meta-analysis at a time.We also performed trim and fill analysis to evaluate the change in pooled estimate when plot asymmetry was accounted for by removing studies with extreme estimates and filling in missing imputed studies based on bias-corrected estimates. 22ubgroup analysis was performed for different types of AF ( paroxysmal vs. non-paroxysmal ) , two main types of ablation energy ( radiofrequency ablation vs. cryoballoon ) , by study design ( prospective vs. retrospective ) , and by study quality ( good vs. fair vs. poor ) .

Sensitivit y a na lysis
To evaluate whether the back transformation method would affect the pooled estimate of binary variables, we performed a sensitivity analysis by repeating the meta-analysis of the incidence of clinical outcomes with logit transformation. 23All analysis was performed using the 'metafor' package in R 24 with a two-tailed p value of < 0.05 considered statistically significant.

Results
We identified 4548 studies published until December 2021 that met the inclusion criteria.After applying exclusion criteria, 73 studies 25 -97 encompassing 67 159 patients were included in the systematic review and meta-analysis ( Figure 1 ) .

Primary outcome
Freedom from at ria l a rrhy t hmia recurrence There was significant heterogeneity among studies regarding the definition of atrial arrhythmia recurrence, blanking period, the followup schedule, as well as methods to record heart rhythm during follow-up time.Most studies considered a blanking period of three months, some considered a period of 2 months, and several did not clearly define the blanking period ( see Supplementary material online Table S2 for more details ) .

Secondary outcomes
Only few studies reported on clinical outcomes other than freedom from atrial arrhythmia recurrence.Therefore, the meta-analysis of these outcomes was performed only in those undergoing multiple procedures where a sufficient sample size was available.Five studies ( 3403 patients ) 25 , 41 , 52 , 76 , 94 reported 5 year mortality and the pooled incidence was 6.0% ( 95% CI 3.1-9.6% ) ( Figure 3 A ) .Stroke or TIA occurred less frequently with a pooled incidence of 2.4% ( 95%CI 1.4-3.7%,from six studies 39 , 52 , 65 , 69 , 86 , 94 of 3057 patients ) ( Figure 3 B ) .Major bleeding occurred with a pooled incidence of 1.2% ( 95% CI 0.7-1.7%,from five studies 39 , 52 , 65 , 69 , 94 of 2715 patients ) ( Figure 3 C ) .Significant heterogeneity was observed for meta-analysis of all-cause death and stroke or TIA ( I 2 of 93.0% and 76.0%, respectively ) , but not for major bleeding ( I 2 was 35.0%, p for heterogeneity = 0.185 ) .Due to the low number of studies reporting these outcomes, subgroup analysis was not performed.
When other outcomes were considered, the incidence of stroke increased from 2.4% at 5 years to 3.8% ( 95% CI 2.9-4.8% ) at 10 years ( Figure 4 B, p value for trend < 0.05 ) .Similarly, the incidence of bleeding increased over time to 2.3% ( 95% CI 1.3-3.6% ) at 10 years following AF ablation ( p value for trends < 0.05 ) .The pooled incidence of mortality beyond 5 years could not be estimated due to insufficient data.

Publication bias
The funnel plots and results of Egger's test to evaluate the risk of publication bias are provided in the Supplementary material online Appendix Figures S1-S5 .Egger's test indicated the presence of funnel plot asymmetry suggesting publication bias ( p < 0.05 ) for meta-analysis of freedom from atrial arrythmia after a single procedure but not after multiple procedures ( p = 0.697 ) .We performed a leave -one -out analysis for the outcome of freedom from atrial arrhythmia recurrence after a single procedure and found no study with a significant effect on the pooled estimate ( Supplementary material online Figure S6 ) .A trim-and-fill analysis showed that the pooled estimate increased to 65.0% ( 95%CI 58.5-71.2% ) when 20 studies were imputed based on bias correction ( see Supplementary material online Figure S7 for the bias-corrected funnel plot ) .All p -values of Egger's test for the meta-analysis of the incidence of mortality, stroke or TIA, and major bleeding were > 0.05, indicating a lack of funnel plot asymmetry suggesting a lack of publication bias.However, the number of studies reporting these outcomes was < 10 and therefore, the ability to detect funnel plot asymmetry with Egger's test was limited.

Sensitivit y a na lysis
When we repeated our analysis using logit instead of Freeman-Tukey double arcsine transformation, there was no significant difference in the pooled results for freedom from atrial arrhythmia after single and multiple procedures ( including subgroup analyses ) , as well as the pooled incidence of mortality, stroke, and bleeding ( Supplementary material online Table S4 ) .

Discussion
In this systematic review, we found that about half of patients undergoing AF ablation remained free from atrial arrhythmia recurrence at 5 years after a single procedure, a success rate that increased to 7 out of 10 patients after multiple AF ablations.Beyond 5 years, freedom from atrial arrhythmia recurrence remained similar over time after a single procedure and marginally declined in patients that underwent multiple ablations, suggesting that recurrence rates largely stabilised beyond 5 years.Freedom from atrial arrhythmia recurrence was higher in patients with paroxysmal AF compared with non-paroxysmal AF, but comparable between radiofrequency and cryoablation, and among different study designs and quality.The pooled incidence of adverse outcomes such as mortality, stroke or TIA, and major bleeding was low.However, the incidence of stroke or TIA and major bleeding continued to rise beyond 5 years despite the seemingly stabilised incidence of atrial arrhythmia freedom, re-enforcing the importance of long-term thromboembolism prevention and bleeding risk management in patients that have undergone catheter ablation.
Long-term outcomes after AF ablation have been reported in a prior review published nearly 10 years ago of 19 publications including 6167 patients, although only a few studies reported outcomes extending to 5 years or more, raising uncertainty about these estimates. 9e extend the literature by systematically summarising procedural outcomes at 5 years or more from more than 70 studies and almost 70 000 patients, incorporating the pooled results from numerous studies published since the prior review. 9Our findings showed that procedural efficacy has remained the same over time, even slightly decreased after multiple ablations.This is perhaps because of the greater use of AF ablation in patients with non-paroxysmal AF, who have lower incidence of freedom from arrythmia recurrence.Another potential explanation for the static procedural efficacy is that none of advances in ablation techniques such as new ablation energy, catheter design, or ablation lesions has been unequivocally proven to have superior efficacy. 99 -101Crucially, our analysis also provides robust data that the risk of atrial arrhythmia recurrence stabilises beyond 5 years as alluded to in the prior review, 9 which affirms the long-term maintenance of AF ablation efficacy.This finding also suggests that those remaining free from atrial arrhythmia 5 years after the procedure could be considered as 'cured' from AF, which has important implications for anticoagulation therapy and for future studies investigating long-term procedural success.The continuation of anticoagulant beyond this period, however, should consider factors other than the arrhythmia status given the evidence showing patients without AF who have high CHA 2 DS 2 -VASc score are also at high risk of thromboembolic events. 102 -104Furthermore, to confidently identify a patient as 'free from atrial arrhythmia recurrence' remains challenging due to the varying definition of arrhythmia recurrence, as well as different methods and frequency of rhythm monitoring.Moreover, symptomatic expression of AF varies among patients with some remaining asymptomatic, adding to the challenge of identifying atrial arrhythmia recurrence.
Although freedom from arrhythmia recurrence is frequently used to measure procedural success and efficacy, other outcomes such as all-cause mortality and stroke or TIA, are well-known clinical endpoints associated with AF. 1 Major bleeding is another important outcome for patients undergoing AF ablation given that most still require long-term OAC for the prevention of thromboembolic events 105 as the current recommendation for OAC continuation is based on individual patient's risk rather than rhythm st atus . 2 To our knowledge, this is the first meta-analysis of these clinical endpoints at 5 years and beyond.The pooled estimates of mortality ( 6.0% by 5 years ) and stroke/TIA ( 2.4% by 5 years ) in our review were lower than reported for patients with AF in general enrolled in clinical trials ( incidence of 3.52-3.94%per year for mortality and 1.27-2.2%per year for stroke ) . 106 , 107Similarly, the incidence of bleeding ( 1.2% by 5 years ) is lower that reported in clinical trials ( 2.71-6.1% per year 106 -108 ) conducted in patients with AF.These observations confirm that patients undergoing AF ablation enjoy better outcomes than the general AF population even though they still face significant risk of AF-associated adverse outcomes.
These findings have several implications for clinical practice.Given freedom from atrial arrhythmia was higher after multiple ablations, clinicians should anticipate the need of multiple procedures to achieve optimal outcomes and routinely counsel patients about such possibility.If patients remain free from atrial arrhythmia at 5 years, then they are likely to remain so beyond this period, meaning that the procedure may be considered as curative in a proportion of patients.The higher success rate in paroxysmal AF also supports emerging evidence suggesting an early rhythm control strategy may lead to better long-term outcomes. 109Ablation energy does not appear to impact long-term efficacy although existing evidence comes mostly from studies using radiofrequency with scant data from other energy sources, highlighting a knowledge gap that needs to be addressed in future studies.Incidence of adverse outcomes such as mortality, stroke or TIA and major bleeding was low, but the risk of stroke or TIA and major bleeding continued to rise after five years despite stabilisation of the rate of freedom from atrial arrhythmia.Continuous management of thromboembolic and bleeding risk in these patients is therefore warranted.Despite these encouraging findings about AF ablation outcomes, the uptake of catheter ablation among AF patients in practice remains low 110 , 111 with significant disparities such as lower rates in females 112 and in public sector hospit als . 113Policies to reduce disparities and make this procedure more accessible to patients should be considered to improve AF outcomes.
This review has limitations that should be considered when interpreting the findings.We excluded all abstracts and conference proceedings, which could introduce publication bias.Indeed, Egger's test indicates the possibility of publication bias in our meta-analysis of freedom from atrial arrhythmia recurrence after a single procedure.Nevertheless, the leave -one -out analysis did not identify any study that significantly affected the pooled estimate, while the trim-and-fill analysis did not find a major change in the pooled estimate.Furthermore, such inclusion ensured that we could extract high-quality and comprehensive data for our meta-analysis.The data manipulation performed ( converting median to mean and combing means of different groups ) may affect the pooled estimate.However, such manipulation was necessary to maximise the number of studies included in the meta-analysis.There was significant heterogeneity among individual publications.Although we could not fully explain the high heterogeneity observed in our meta-analysis, it could be likely attributed to the significant differences among individual studies in terms of outcome definition, follow-up schedule and method, as well as results reporting.

Figure 1
Figure 1 Study selection flow diagram.

Figure 2
Figure 2 Freedom from atrial arrhythmia recurrence at 5 years following catheter ablation of atrial fibrillation: ( A ) after a single procedure and ( B ) after multiple procedures.

Figure 2
Figure 2 Continued

Figure 3
Figure 3 Other clinical outcomes at five years following catheter ablation of atrial fibrillation: ( A ) all-cause mortality; ( B ) stroke or transient ischaemic attack; and ( C ) major bleeding.

Figure 4
Figure4Outcomes at 5 years and beyond following catheter ablation of atrial fibrillation. (A ) freedom from atrial arrhythmia recurrence and ( B ) incidence of stroke or transient ischaemic attack and major bleeding.